Innate host restriction barriers are major impediments to human immunodeficiency virus type 1 (HIV-1) replication in macaque species. However, the mechanisms of restriction remain incompletely understood. The goal of this application is to further characterize the replicative properties of macaque-tropic HIV-1 variants in vitro in order to gain a further understanding of adaptive viral mutations that may be important for escaping host restriction factors and establishing persistent infection and causing disease in the macaque host. We recently demonstrated that pig-tailed macaques are uniquely susceptible to HIV-1 infection because they do not express TRIM5?. Consequently, they can be persistently infected with a novel macaque-tropic HIV-1 clone that is chimeric for the SIV vif (HSIV-vif) and capable of counteracting the pig-tail restriction factors APOBEC3G and 3F. However, while infection by HSIV-vif is persistent for years, replication is very low compared to pathogenic SIV. Our preliminary data show that this may in part be due to the inability of the HIV- 1 strain used for the in vivo infection to escape the effects of type I interferon (IFN) induced innate restriction i pig-tail CD4+ T-cells. In preliminary studies, we have identified an HIV-1 clone that can escape type I interferon induced restriction in pig-tail CD4+ T-cells. We therefore hypothesize that HIV-1 variants may evolve that are capable of overcoming innate restriction in pig-tail CD4+ T-cells, leading to increased replication. The experiments proposed in this application will dissect the viral determinants that enable some variants of HIV-1 to persistently replicate in pig-tail CD4+ T-cells in a type I interferon-induced restrictive state. They will also further examine the cellular factors contributing to restriction. If successful, these studies should provide valuable insight ito HIV-1-host interactions influencing transmission and disease. Ultimately, the studies should inform the development of a macaque-model of HIV-1 pathogenesis.